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Copper binding to the Alzheimer's disease amyloid precursor protein.

Kong GK, Miles LA, Crespi GA, Morton CJ, Ng HL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW - Eur. Biophys. J. (2007)

Bottom Line: Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease.We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD.Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production.

View Article: PubMed Central - PubMed

Affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.

ABSTRACT
Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.

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Related in: MedlinePlus

Model of the APP growth factor domain docked onto CuBD. Note that an extra β-strand (coloured yellow), suggested by the modelling, has been inserted between the two domains to form an extended sheet
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Fig5: Model of the APP growth factor domain docked onto CuBD. Note that an extra β-strand (coloured yellow), suggested by the modelling, has been inserted between the two domains to form an extended sheet

Mentions: The N-terminal GFD is immediately upstream of CuBD (Fig. 1) and together they constitute the cysteine-rich region of the molecule. To determine if these two domains likely interact we used the GRAMM program (Vasker and Aflalo 1994; Vasker 1996) to dock CuBD to the crystal structure of GFD (PDB id: 1MWP; Rossjohn et al. 1999). Visual inspection indicated that the most plausible domain pair structure brought the C-terminus of GFD and the N-terminus of CuBD in close proximity while the arrangement of the domain interface was suggestive of a continuation of the β-sheet from domain 1 into the β-sheet of domain 2 (Fig. 5). The total surface area buried in forming the interface is ∼200 Å2. The residues forming the interface are primarily hydrophobic, including Val86, Leu118, Val119 and Gly120 from GFD and Ala126, Leu127, Leu128, Val129 and Pro130 of CuBD with the ends of this hydrophobic region flanked by polar and charged residues that are exposed to solvent. In total there are nine potential hydrogen bonds and 28 van der Waals interactions in the domain interface. Both the heparin binding site of GFD and the copper binding site of CuBD, are exposed in the model at opposite ends of the cysteine rich region, separated by ∼50 Å.Fig. 5


Copper binding to the Alzheimer's disease amyloid precursor protein.

Kong GK, Miles LA, Crespi GA, Morton CJ, Ng HL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW - Eur. Biophys. J. (2007)

Model of the APP growth factor domain docked onto CuBD. Note that an extra β-strand (coloured yellow), suggested by the modelling, has been inserted between the two domains to form an extended sheet
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921068&req=5

Fig5: Model of the APP growth factor domain docked onto CuBD. Note that an extra β-strand (coloured yellow), suggested by the modelling, has been inserted between the two domains to form an extended sheet
Mentions: The N-terminal GFD is immediately upstream of CuBD (Fig. 1) and together they constitute the cysteine-rich region of the molecule. To determine if these two domains likely interact we used the GRAMM program (Vasker and Aflalo 1994; Vasker 1996) to dock CuBD to the crystal structure of GFD (PDB id: 1MWP; Rossjohn et al. 1999). Visual inspection indicated that the most plausible domain pair structure brought the C-terminus of GFD and the N-terminus of CuBD in close proximity while the arrangement of the domain interface was suggestive of a continuation of the β-sheet from domain 1 into the β-sheet of domain 2 (Fig. 5). The total surface area buried in forming the interface is ∼200 Å2. The residues forming the interface are primarily hydrophobic, including Val86, Leu118, Val119 and Gly120 from GFD and Ala126, Leu127, Leu128, Val129 and Pro130 of CuBD with the ends of this hydrophobic region flanked by polar and charged residues that are exposed to solvent. In total there are nine potential hydrogen bonds and 28 van der Waals interactions in the domain interface. Both the heparin binding site of GFD and the copper binding site of CuBD, are exposed in the model at opposite ends of the cysteine rich region, separated by ∼50 Å.Fig. 5

Bottom Line: Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease.We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD.Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production.

View Article: PubMed Central - PubMed

Affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.

ABSTRACT
Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.

Show MeSH
Related in: MedlinePlus